RFB4(dsFv)-PE38 (BL22) is a recombinant disulfide-stabilized
immunotoxin composed of the variable domains (VH and VL) of the anti-CD22
monoclonal antibody RFB4 attached by a disulfide bond and with VH fused to
truncated Pseudomonas exotoxin. A total of 31 patients with
chemotherapy-refractory hairy cell leukemia (HCL), chronic lymphocytic leukemia
(CLL), or non-Hodgkin’s lymphoma have received 99 cycles of BL22 at 3 to 50
µg/kg IV every other day for 3 doses (qod × 3).

The most common toxicities were hypoalbuminemia, third-spacing
of fluid without pulmonary edema, nausea, transaminase elevations, and myalgias.
Toxicity was prevented by anti-inflammatory agents and hydration. The 50 µg/kg
qod × 3 level was considered dose limiting because one patient developed
reversible hemolytic uremic syndrome (HUS) and most other patients had grade 1
creatinine elevation or proteinuria, which was considered a risk factor for HUS.
The maximum tolerated dose was 40 µg/kg qod × 3, where all 18 cycles in 10
patients were well tolerated. Only 1 out of 31 patients made neutralizing
antibodies after 1 cycle, and this patient had preexisting neutralizing
antibodies.

Out of 11 purine analog-refractory HCL patients who are
evaluable for response, 10 patients achieved complete remission (91% CR) and 1
patient had a partial response (9% PR). All 3 patients with variant HCL (HCLv)
had never been in CR with previous chemotherapy but had CR to BL22. Complete
remissions were induced after one cycle in 5 of the patients, and 5 required two
to nine cycles to achieve CR. Of the 10 in CR, minimal residual disease by flow
cytometry was eliminated in the blood in 10 and in the marrow in 3. Complete
remissions were most rapid in patients with mono- or oligoclonal elevations in
cytotoxic T cells, which often increased with repeated cycles. No patients in CR
have relapsed after up to 1 year of follow-up, based on restaging including bone
marrow biopsy.

CONCLUSION: BL22 showed clinically useful effects in CLL with
reductions of circulating CLL cells (> 99.9% in 1 patient) and lymph nodes,
although CRs have not yet been observed. Thus BL22 is the first agent since
purine analogs that is capable of inducing CR in the majority of patients with
HCL, and is the only agent that can induce CR in most patients with
chemotherapy-refractory or variant HCL. Its sparing of T cells may also allow
improved clearing of minimal residual disease.